PROJECT SUMMARY (Project 3 - Cassis) Recent studies demonstrate a strong association between serum levels of polychlorinated biphenyls (PCBs) and an increased odds ratio for type 2 diabetes (T2D). This proposal tests the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhR) to increase expression of proinflammatory cytokines, resulting in reductions in glucose uptake and the development of insulin resistance. Further, we hypothesize that the polyphenol, resveratrol, can be used to prevent and/or treat PCB-induced elevations in adipocyte proinflammatory cytokine expression and impaired glucose homeostasis during weight loss. We demonstrated that administration of coplanar PCBs to low fat fed male and female mice induces glucose and insulin intolerance associated with adipose-specific elevations in tumor necrosis factor-? (TNF-?). Remarkably, when mice were made obese from consumption of a high fat (HF) diet, effects of PCB to impair glucose homeostasis were lost when lipophilic PCBs were sequestered at higher levels within adipose tissue lipids. However, upon weight loss, PCBs impaired glucose and insulin tolerance, limiting beneficial effects of weight loss to improve glucose homeostasis. These results suggest that obesity increases body burden of PCBs, and that release of PCBs during weight loss from adipose lipids may be harmful in the context of T2D. The anti-oxidant polyphenol and putative AhR antagonist, resveratrol, abolished acute effects of PCBs to impair glucose tolerance in mice, and protected against PCB-induced reductions in insulin signaling and glucose uptake in adipocytes. Aim 1 will define the role of adipocyte AhR in PCB-induced impairment of glucose and insulin tolerance in lean male and female mice, and in obese mice experiencing weight loss. Results from these studies will define whether the enhanced accumulation of lipophilic PCBs to adipose tissue results in adipocyte-specific impairment of glucose uptake. Aim 2 will define the adipocyte-specific effects of resveratrol on PCB-induced impairment of glucose homeostasis in obese male and female mice exhibiting weight loss. Results from this aim will determine if resveratrol acts to protect against PCB-induced impairment of glucose uptake and insulin resistance through an adipocyte-specific mechanism, and whether this therapeutic strategy have utility in the setting of weight loss. The impact of this research is identification of mechanisms linking PCB exposures to T2D and development of a therapeutic strategy, resveratrol, to protect against harmful effects of PCBs on glucose homeostasis in lean subjects, as well as obese subjects experiencing weight loss.